Bipolar disorder affects up to 3% of the population and is one of the top 10 causes of disability worldwide, yet the underlying neurophysiologic causes of the disorder remain elusive. The fluctuation of emotion that is the disorder's hallmark suggests a dysfunction of brain networks that normally maintain emotional homeostasis. Recent neuroimaging studies that have combined fMRI with neuropsychological paradigms known to activate limbic structures have revealed limbic hyperarousal and orbitofrontal hypoactivation in bipolar subjects, when manic and even when euthymic. Whether this persistent limbic hyperreactivity represents an abnormality in local neuronal function or an abnormality in an inhibitory connection to limbic structures remains to be fully elucidated. In this application we propose to use novel techniques to assess the relationship between white matter integrity and neuronal function. Using DTI-tractography we will examine white matter connections between brain regions (anatomical connectivity) in the same persons for which we simultaneously collect functional (fMRI) data. We will specifically look for abnormalities in structural white matter connections between the amygdala and orbitofrontal cortex that may explain increased amygdala function and reduced OFC-amygdala functional connectivity seen in prior studies. Collection of white matter tract data and functional neuroimaging data at the same time in the same subjects has never before been reported in the bipolar population. The results of this exploratory analysis could significantly advance our knowledge about the etiology of functional abnormalities of the brain seen in bipolar disorder. Results from these exploratory data could lay the groundwork for a future R01 application. PUBLIC HEALTH RELEVANCE: Bipolar illness is one of the top 10 causes of disability worldwide, yet the underlying neurophysiologic causes of the disorder remain unknown. In the proposed study we will use novel research tools to concomitantly obtain "structural" neuroimaging data of the white matter tracts that interconnect neurons and "functional" neuroimaging data that indicates level of neuron activity in different brain regions to determine the relationship, if any, between abnormal brain structure and abnormal brain function. This has the potential to markedly advance our understanding of underlying neurophysiologic causes of brain abnormalities in bipolar illness.